Insufficient oxygenation of the blood (hypoxemia) is a common symptom in ICU patients, and may be caused by a combination of four different pathologies: 1) decreased alveolar ventilation (hypoventilation), 2) oxygen diffusion limitation, 3) inequality in ventilation/perfusion, and 4) shunts. Hypoxemia can be assessed by any of the following physiological parameters: 1) arterial PO2 and PCO2, 2) difference in alveolar and arterial PO2, 3) venous admixture (known as a physiological shunt), and 4) physiological dead space. However, while these parameters are clinically useful, they offer quite limited information and are subject to misinterpretation when the underlying assumptions are not met. For the most part, the exact causes of hypoxemia are difficult to distinguish in any given patient using presently available tools. A multiple inert gas elimination technique (MIGET) was introduced in the early 1970s as a way to overcome many of the limitations imposed by the classical methods mentioned above. The uniqueness of MIGET is its use of inert gas data to quantitate the many pathological features of O2 and CO2 gas exchange in the acutely ill. Taking advantage of simpler gas exchange models applied to inert gases (compared to O2 and CO2), MIGET provides quantitative distributions of ventilation and blood flow with respect to V&/ Q&ratio. It is the acquisition of these distributions that form the basis for the many calculations of O2 and CO2 gas exchange parameters that MIGET provides. Importantly, a special strength of MIGET is that it distinguishes regions of low V&A / Q&ratio from unventilated regions (shunt), and also regions of high V&A / Q&ratio from unperfused lung. MIGET also allows additional insights into gas exchange, which include 1) identification of the presence of diffusion limitation for O2, and 2) quantification of the role of extrapulmonary factors on arterial PO2 and PCO2 gas exchange limitation. However, MIGET has never evolved from a research tool to a clinical management tool due to: 1) measurement time delays;2) operational complexity;and 3) substantial invasiveness. The goal of this proposed work is to develop and validate the instrumentation and methodology that provides the complex V&/ Q&distribution and analysis of MIGET - but without the cited disadvantages. PUBLIC HEALTH RELEVANCE: For over 30 years, MIGET (Multiple Inert Gas Elimination Technique) has been a valuable research tool used to understand and characterize lung abnormalities. Physiological information from this technique could greatly improve therapy in the Intensive Care Unit (ICU), but the highly invasive methods make it impractical in any clinical setting. This proposed Non-Invasive MIGET System (NIMS) has the potential to provide MIGET information to improve patient management both in and outside of the ICU.